Metastasis of cancer cells from the primary site to distant organs is a major cause of cancer-related death, as current chemotherapies are largely ineffective against metastasis. Recent data from the PIs' lab suggest that colorectal cancer (CRC) cells may undergo remarkable metabolic reprogramming after they metastasize to liver, which is the most common site for CRC metastasis. This discovery makes the conceptual argument that altered metabolism may contribute to metastatic phenotypes. The proposed study will use an integrative systems approach to understand metabolic reprogramming of CRC liver metastasis. Primary and liver tumors from an in vivo CRC metastasis model will be profiled by RNA-seq and high-resolution, liquid chromatography-mass spectrometry (LC-MS) based metabolomics. Integrated network analysis of the transcriptome and metabolome will identify altered metabolic pathways in CRC metastases. The findings will be corroborated by an extensive clinical biobank that contains a large collection of CRC liver metastases. Based on the integrative systems analysis, this study will then explore the hypothesis that manipulation of metabolic reprogramming will interfere with growth of CRC liver metastasis. Preliminary data suggest that targeting dysregulated metabolism, which includes inhibition of enzymes and restrictive diets, can interfere with growth of liver metastases more than frontline chemotherapy can in animal models. Since metastatic tumor cells have to adapt to their new microenvironment, targeting metabolic reprogramming of metastasis may be a viable approach for multiple cancer types and a significant percentage of the patient population.